Differences of humoral and cellular immune response to an acellular pertussis booster in adolescents with a whole cell or acellular primary vaccination

To study the pertussis-specific immune response of adolescents with different prevaccination schedules, we measured the humoral and cell-mediated immunity (CMI) to pertussis antigens before and after a five-component Tdap booster vaccination in 78 adolescents, who had previously received either five doses of a two-component acellular pertussis vaccine (aP; last dose age 4-6 years), four doses of aP (last dose age 18-24 months), or four doses of whole cell pertussis vaccine (wcP; last dose age 18-24 months). The proportion of participants with a twofold rise in titre was 79% against pertussis toxin (PT), 94% against filamentous hemagglutinin (FHA), and 99% against pertactin (PRN) without significant differences between the three groups. However, participants with primary wcP vaccination showed higher postvaccination titres to pertussis toxin (geometric mean titre, GMT 50.3EU/ml) than those with either four (GMT 17.1EU/ml) or five (GMT 16.4EU/ml) previous aP doses. CMI indices to PT, FHA, PRN and fimbriae (FIM) increased after vaccination and were similar between groups. The current adolescent Tdap booster immunization induced good humoral and cellular immune response to pertussis. The higher antibody titres to pertussis toxin may indicate a more effective priming of B cell memory after primary whole-cell vaccination.     

Pertussis vaccination during pregnancy in Belgium: Results of a prospective controlled cohort study

Vaccination during pregnancy has been recommended in some countries as a means to protect young infants from severe infection. Nevertheless, many aspects are still unknown and possible blunting of the infant's immune responses by maternal antibodies, is one of the concerns with maternal vaccination. We report the first prospective controlled cohort study in women and infants on the effects of using Boostrix^®, a combined tetanus, diphtheria and acellular pertussis vaccine, during pregnancy. The primary aim was to measure the influence of this booster dose on the titer and duration of the presence of maternal antibodies in the infants and assess possible interference with infant immune responses.In a controlled cohort study, 57 pregnant women were vaccinated with Tdap vaccine (Tetanus Diphtheria acellular Pertussis, Boostrix, GSK Biologicals), at a mean gestational age of 28.6 weeks. A control group of pregnant women (N = 42) received no vaccine. Antibody geometric mean concentrations (GMCs) against tetanus (TT), diphtheria (DT), pertussis toxin (PT), filamentous haemagglutinin (FHA) and pertactin (Prn) were measured with commercial ELISA tests in samples taken preceding maternal vaccination and one month afterwards, at delivery and from the cord blood, and in infants before and 1 month after the primary series of 3 pertussis containing hexavalent vaccines.Infants born to vaccinated women had significantly higher GMC at birth and during the first 2 months of life for all vaccine antigens compared to the offspring of unvaccinated women, thereby closing the susceptibility gap for pertussis in infants. However, blunting was noticed for infant diphtheria and pertussis toxin vaccine responses (p < 0.001) in the infants from vaccinated women after the primary vaccination schedule (weeks 8,12 and 16).Since pertussis vaccination has been recommended during pregnancy already, the results of this study support that recommendation and provide additional scientific evidence to document possible interference by maternal antibodies.     

Pertussis vaccination during pregnancy in Vietnam: Results of a randomized controlled trial Pertussis vaccination during pregnancy

A pertussis vaccination during pregnancy has recently been adopted in several countries to indirectly protect young infants. This study assessed the effect of adding a pertussis component to the tetanus vaccination, in the pregnancy immunization program in Vietnam.A randomized controlled trial was performed. Pregnant women received either a Tdap (tetanus, diphtheria acellular pertussis) vaccine or a tetanus only vaccine between 19 and 35 weeks’ gestational age. Immunoglobulin G (IgG) against tetanus (TT), diphtheria (DT), pertussis toxin (PT), filamentous hemaglutinin (FHA) and pertactin (Prn) were measured using commercial ELISA tests, at baseline, 1 month after maternal vaccination, at delivery, and in infants from cord blood and before and after the primary series (EPI: month 2-3-4) of a pertussis containing vaccine.Significantly higher geometric mean concentrations (GMC) were observed for all 3 measured pertussis antigens in the offspring of the Tdap group, up to 2 months of age. One month after completion of the primary infant vaccination schedule, anti-Prn GMC, but not anti-PT and anti-FHA GMCs, was significantly (p = 0.006) higher in the control group.Maternal antibodies induced by vaccination during pregnancy close the susceptibility gap for pertussis in young infants. Limited interference with the infant vaccine responses was observed. Whether this interference effect disappears with the administration of a fourth vaccine dose is further studied.     

An observational study of antibody responses to a primary or subsequent pertussis booster vaccination in Australian healthcare workers

Adult pertussis vaccination is increasingly recommended to control pertussis in the community. However, there is little data on the duration and kinetics of immunity to pertussis boosters in adults. We compared IgG responses to vaccination with a tetanus, low-dose diphtheria, low-dose acellular pertussis (Tdap) booster at 1 week, 1 month and 1 year post-vaccination in whole-cell (wP)-primed Australian paediatric healthcare workers who had received an adult Tdap booster 5–12 years previously, to those who received their first Tdap booster.Tdap vaccination was well tolerated in both groups. Previously boosted adults had significantly higher pre-vaccination IgG concentrations for all vaccine-antigens, and more were seropositive for pertussis toxin (PT)-specific IgG (≥ 5 IU/mL) (69.5%; 95% confidence interval (CI) 59.5–79.5) than adults in the naïve group (45.2%; 95% CI 32.8-57.5). Tdap vaccination significantly increased IgG responses 1 month post-vaccination in both groups. This increase was more rapid in previously boosted than in naïve adults, with geometric mean fold-increases in PT-IgG at 1 week post vaccination of 3.6 (95% CI 2.9–4.3) and 2.6 (95% CI 2.2–3.2), respectively. Antibody waning between 1 month and 1 year post-vaccination was similar between groups for IgG specific to PT and filamentous haemagglutinin (FHA), but was faster for IgG against pertactin (PRN) in the naïve group (GMC ratio 0.36; 95% CI 0.31–0.42) than the previously boosted group (GMC ratio 0.45; 95% CI 0.39–0.50). At baseline, all but one adult had protective IgG titres against tetanus toxin (TT) (≥ 0.1 IU/mL), and 75.6% in the previously boosted and 61.3% in the naïve group had protective IgG titres against diphtheria toxoid (DT) of ≥ 0.1 IU/mL.This study shows that pertussis immune memory is maintained up to 12 years after Tdap vaccination in wP-primed Australian adults. There was no evidence that pertussis immune responses waned faster after a booster dose. These findings support current recommendations of repeating Tdap booster vaccination in paediatric healthcare workers at least every 10 years. Clinical trials registry: ACTRN12615001262594.     

Reactogenicity and immunogenicity of tetanus toxoid,reduced diphtheria toxoid,and acellular pertussis vaccine (Tdap) in pregnant and nonpregnant women

ObjectiveTetanus toxoid, reduced diphtheria toxoid, and acellular pertusiss (Tdap) vaccine is recommended during each pregnancy, regardless of prior receipt. Data on reactogenicity and immunogenicity, particularly after repeated Tdap, are limited. We compared local injection-site and systemic reactions and serologic response following Tdap in (1) pregnant and nonpregnant women and (2) pregnant women by self-reported prior Tdap receipt.Study designPregnant women (gestational age 20–34 weeks) and nonpregnant women receiving Tdap were enrolled in this observational study. Injection-site and systemic reactions were assessed for one week post-vaccination. Pertussis toxin, filamentous hemagglutinin, pertactin, fimbriae, tetanus and diphtheria specific IgG antibody titers were determined by standardized enzyme-linked immunosorbent assay at baseline and 28 days post-vaccination. Reactogenicity and serologic responses were compared by pregnancy status, and within pregnant women by self-reported prior Tdap receipt.Results374 pregnant and 225 nonpregnant women were vaccinated. Severe local or systemic reactions or “any” fever were uncommon (≤3% for both groups). Moderate/severe injection-site pain was significantly higher in pregnant (17.9%) versus nonpregnant (11.1%) women, but did not prompt a healthcare visit. Proportions of other moderate/severe or any severe reactions were not significantly higher in pregnant compared to nonpregnant women. Moderate/severe (including pain) and severe reactions were not significantly higher in pregnant women receiving repeat versus first-time Tdap. Antibody titers increased from baseline to post-vaccination for all vaccine antigens in pregnant and nonpregnant women; post-vaccination titers against pertussis toxin and filamentous hemagglutinin were significantly higher in nonpregnant versus pregnant women (p < 0.01).ConclusionTdap was well-tolerated in pregnant and nonpregnant women. Pregnant women were more likely to report moderate/severe pain at the Tdap injection-site compared with nonpregnant women, but did not necessitate medical visits. Prior Tdap receipt did not increase occurrence of moderate/severe local or systemic reactions in pregnant women. Serologic responses to all vaccine antigens were robust.Clinical Trial Registration@ClinicalTrials.gov. NCT02209623.https://clinicaltrials.gov/ct2/show/NCT02209623.     

Impact of pregnancy on polyfunctional IgG and memory B cell responses to Tdap immunization

BackgroundMaternal pertussis immunization using Tdap vaccine is recommended in many countries to protect newborns from severe post-natal infection. Immunological changes during pregnancy may influence the response to vaccines. The quality of IgG and memory B cell responses to Tdap immunization in pregnant women has not yet been described.MethodsThe impact of pregnancy on the response to Tdap vaccination was assessed by comparing humoral immune responses in 42 pregnant and 39 non-pregnant women. The levels of serum pertussis antigens and tetanus toxoid-specific IgG, IgG subclasses, IgG Fc-mediated effector functions, as well as memory B cell frequencies were assessed before and at several time points after vaccination.ResultsTdap immunization induced similar levels of pertussis and tetanus-specific IgG and IgG subclasses in pregnant and non-pregnant women. Pregnant women produced IgG promoting complement deposition, and neutrophils and macrophages phagocytosis at levels comparable to non-pregnant women. They were also able to expand pertussis and tetanus-specific memory B cells at similar frequencies as non-pregnant women, suggesting equivalent “boostability”. Higher levels of vaccine-specific IgG, IgG subclasses, and IgG Fc-mediated effector functions were detected in cord blood as compared to maternal blood, indicating efficient transport across the placenta.ConclusionsThis study demonstrates that pregnancy does not affect the quality of effector IgG and memory B cell responses to Tdap immunization and that polyfunctional IgG are efficiently transferred across the placenta.Registry's URL and the trial's registration numberClinicalTrials.Gov (NCT03519373).     

Immunogenicity,transplacental transfer of pertussis antibodies and safety following pertussis immunization during pregnancy: Evidence from a randomized,placebo-controlled trial

BackgroundPertussis immunization during pregnancy is recommended in many countries. Data from large randomized controlled trials are needed to assess the immunogenicity, reactogenicity and safety of this approach.MethodsThis phase IV, observer-blind, randomized, placebo-controlled, multicenter trial assessed immunogenicity, transplacental transfer of maternal pertussis antibodies, reactogenicity and safety of a reduced-antigen-content diphtheria-tetanus-three-component acellular pertussis vaccine (Tdap) during pregnancy. Women received Tdap or placebo at 27–36 weeks’ gestation with crossover ≤ 72-hour-postpartum immunization. Immune responses were assessed before the pregnancy dose and 1 month after, and from the umbilical cord at delivery. Superiority (primary objective) was reached if the lower limits of the 95% confidence intervals (CIs) of the pertussis geometric mean concentration (GMC) ratios (Tdap/control) in cord blood were ≥ 1.5. Solicited and unsolicited adverse events (AEs) and pregnancy-/neonate-related AEs of interest were recorded.Results687 pregnant women were vaccinated (Tdap: N = 341 control: N = 346). Superiority of the pertussis immune response (maternally transferred pertussis antibodies in cord blood) was demonstrated by the GMC ratios (Tdap/control): 16.1 (95% CI: 13.5–19.2) for anti-filamentous hemagglutinin, 20.7 (15.9–26.9) for anti-pertactin and 8.5 (7.0–10.2) for anti-pertussis toxoid. Rates of pregnancy-/neonate-related AEs of interest, solicited general and unsolicited AEs were similar between groups. None of the serious AEs reported throughout the study were considered related to maternal Tdap vaccination.ConclusionsTdap vaccination during pregnancy resulted in high levels of pertussis antibodies in cord blood, was well tolerated and had an acceptable safety profile. This supports the recommendation of Tdap vaccination during pregnancy to prevent early-infant pertussis disease.Clinical Trial Registration. ClinicalTrials.gov: NCT02377349.     

Acquisition of specific antibodies and their influence on cell-mediated immune response in neonatal cord blood after maternal pertussis vaccination during pregnancy

Maternal immunization with pertussis acellular vaccine (Tdap) is an intervention that provides protection to newborns. However, it has been reported that high maternal antibody levels may adversely affect the immune response of infants after active immunization. In this study, we evaluated neonatal passive acquisition of pertussis-specific antibodies and their influence on the neonatal cell-mediated immune response.Pregnant women were either vaccinated with Tdap vaccine (case group, n?=?66) or received no vaccine (control group, n?=?101). Whole-cell Bordetella pertussis (Bp), pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN)-specific serum IgG were quantified in paired maternal-cord sera, and Bp- and PT-specific IgA were evaluated in colostrum by ELISA. Ex vivo neonatal blood lymphocyte responsiveness after Bp stimulation was assessed in case (n?=?17) and control (n?=?15) groups using flow cytometry to detect proliferation, cytokine production and activation phenotype of lymphocytes in the context of high specific IgG acquired after maternal vaccination.Anti-Bp, PT, FHA and PRN IgG concentrations in maternal and cord sera from case group were higher than those in control group with positive correlation indexes in both groups for all pertussis antigens. The control group presented higher placental transfer ratios of specific antibodies and, in the case group, vaccination between 26 and 31 gestation weeks was associated with the best placental transfer ratios. Specific IgA concentrations in colostrum were not affected by vaccine status. Whole blood assays revealed that newborns responded to Bp stimulation with higher expression of CD40L, CD69 and CD4⁺ T cell proliferation compared to unstimulated cells, and a lower Th1 response, while a preserved Th2 response compared to adults, but there were no differences between the neonatal groups for any of the studied parameters.Our results indicate that higher pertussis-specific IgG levels in newborn sera after maternal vaccination do not affect the neonatal ex vivo cell-mediated immune response.     

The induction of breast milk pertussis specific antibodies following gestational tetanus–diphtheria–acellular pertussis vaccination

Background

Center for Disease Control and Prevention recommends vaccination of pregnant women with tetanus–diphtheria–acellular pertussis (Tdap).

Aim

To measure pertussis specific antibodies, total protein and their ratio in breast milk following gestational Tdap vaccination.

Methods

Women who received Tdap after the 20th week of pregnancy were recruited and unvaccinated women served as controls. Breast milk total protein, immunoglobulin A (IgA) to pertussis toxin (PT), filamentous hemagglutinin (FHA) and immunoglobulin G (IgG) to PT, FHA and pertactin (PRN) were measured. To overcome the dilution that occurs in the transition from colostrum to mature breast milk, we calculated pertussis specific antibody to total protein ratio.

Results

Pertussis specific IgA was the predominant pertussis immunoglobulin in the colostrum of Tdap vaccinated women with the geometric mean concentrations (GMCs) of IgA to FHA higher than for IgA to PT, 24.12 ELISA units/milliliter (EU/mL) vs. 8.18 EU/mL, respectively, p < 0.004. There were differences between the vaccinated women and controls in the GMCs of IgA to FHA and IgG to PRN in the colostrum, 24.12 EU/mL vs. 6.52 EU/mL, p = 0.01 and 2.46 EU/mL vs. <0.6 EU/mL, p = 0.03, respectively. The GMCs of total protein showed significant decline over 8 weeks in the vaccinated women and controls, p < 0.004. Among vaccinated women, there was significant decline in the GMCs of IgA to PT and FHA over 8 weeks, p < 0.001. The geometric mean ratio of IgA to FHA to total protein also declined significantly over 8 weeks in the vaccinated women, p < 0.01, demonstrating a true decrease, however, pertussis IgA was measurable at 8 weeks.

Conclusions

Select colostrum pertussis antibody levels were significantly higher among women vaccinated with Tdap during pregnancy compared with unvaccinated women. Among vaccinated women, maximal levels of pertussis specific IgA were in the colostrum but still detected at 8 weeks. Lactation may augment infant's protection against pertussis.     

Long-term immunogenicity of a single dose of acellular pertussis vaccine in paediatric health-care workers

OBJECTIVE: Monitor the long-term immunogenicity of a single dose of acellular pertussis vaccine in health-care workers. DESIGN: German health-care workers and child-care workers received a single dose of a monovalent acellular pertussis vaccine (PAC-Mérieux) in an open-label study. Blood samples were taken before (n=261), 4 weeks after (n=246), 1 year (n=187), 2 years (n=53), 3 years (n=134) and 4 years (n=37) after vaccination. IgG- and IgA-anti-pertussis-toxin (PT), IgG- and IgA-anti-filamentous hemagglutinin (FHA), and IgG-anti-pertactin (PRN) were measured by ELISA. RESULTS: Of all subjects, 97.1%, 99.2% and 97.2% had an antibody response to PT, FHA and PRN, respectively. Four weeks after vaccination the median titres of IgG antibodies to PT, FHA and PRN were 314, 785 and 84 EU/l, respectively, and all vaccinees had an immune response to at least one pertussis antigen. IgA-anti-PT and IgA-anti-FHA responses were found in 63.4% and 96.3% of subjects with a median titre of 30 and 196 EU/ml, respectively. The titre of IgG-anti-PT decreased slowly with a median concentration of 76, 71, 71 and 63 EU/ml after 1, 2, 3 and 4 years, respectively. Secondary titre increases were observed in 0.5%, 3.3%, 5.6% and 12.5% of the vaccinees 1, 2, 3, and 4 years after vaccination. CONCLUSION: In German health paediatric care workers long-lasting immune responses with high antibody levels could be induced by a single dose of acellular pertussis vaccine. A renewed contact with B. pertussis antigens resulted in a measurable immune response to PT between 0.5% (1 year p.v.) and 12.5% (4 years p.v.).     

Pertussis vaccination during pregnancy in Belgium: Follow-up of infants until 1 month after the fourth infant pertussis vaccination at 15 months of age

Vaccination of pregnant women with a pertussis containing vaccine is a recommended strategy in some industrialized countries, to protect young infants from severe disease. One of the effects of the presence of high titers of passively acquired maternal antibodies in young infants is blunting of immune responses to infant vaccination. We present infant immune responses to a fourth pertussis containing vaccine dose at 15 months of age, as a follow-up of previously presented data.In a prospective cohort study, women were either vaccinated with an acellular pertussis vaccine (Boostrix^®) during pregnancy (vaccine group) or received no vaccine (control group).All infants were vaccinated with Infanrix Hexa^® according to the standard Belgian vaccination schedule (8/12/16 weeks, 15 months). We report results from blood samples collected before and 1 month after the fourth vaccine dose. Immunoglobulin G (IgG) antibodies against pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (Prn), tetanus toxoid (TT) and diphtheria toxoid (DT) were measured using commercially available ELISA tests. Antibody levels were expressed in International Units per milliliter.Demographic characteristics were similar in the vaccine and control group. Before the fourth vaccine dose, significantly lower antibody titers were measured in the vaccine group compared to the control group for anti-Prn IgG (p = 0.003) and anti-DT IgG (p = 0.023), with a steep decay of antibody titers since post-primary vaccination. One month after the fourth dose, antibody titers were only significantly lower in the vaccine group for anti-PT IgG (p = 0.006). For all antigens, there was a rise in antibody titer after the fourth vaccine dose.The present results indicate still a minor blunting effect 1 month after a fourth vaccine dose for anti-PT antibodies. However, a good humoral immune response on all measured antigens was elicited in both groups of children. The clinical significance of such blunting effect is yet unknown.Clinicaltrials.gov identifier: NCT01698346.     

Kinetics of maternal pertussis-specific antibodies in infants of mothers vaccinated with tetanus,diphtheria and acellular pertussis (Tdap) during pregnancy

BackgroundKinetics of Tdap-induced maternally-derived antibodies in infants are poorly understood. Pre-Tdap era data suggest that maternal pertussis antibodies in infants have a half-life of approximately 5–6 weeks.Methods34 mother-infant pairs had blood collected before maternal Tdap vaccination, 4 weeks later, at delivery (maternal and cord), and at infant ages 3 and 6 weeks from June 2014-March 2015. Immunoglobulin G (IgG) to pertussis toxin (PT), filamentous hemagglutinin (FHA), fimbrial proteins (FIM) and pertactin (PRN) was quantified by multiplex luminex assay (IU/ml). Geometric mean concentrations (GMCs) with 95% confidence intervals (C.I.) and half-life of pertussis antibodies were calculated.ResultsTdap was administered to 34 women (mean age 31.1 years) at mean gestation 30.7 weeks (28–32.7). Mean neonatal gestation was 39.1 weeks (36–41.1) and mean birthweight was 3379 g (2580–4584). Four weeks post-Tdap vaccination, maternal pertussis-specific IgG GMCs increased ≥4-fold in 59%, 41%, 29% and 44% of women for PT, FHA, FIM and PRN, respectively, and then waned. The transplacental transport ratio of pertussis antibodies was 1.35 for PT, 1.41 for FHA, 1.31 for FIM and 1.36 for PRN. Between birth and age 6 weeks, infant serum GMC for PT-specific IgG decreased from 55.1 IU/mL (38.6–78.6) to 21.1 IU/ml (14.7–30.2), and the proportion of infants with PT levels ≥10 IU/ml fell from 97% to 67%. Half-life of pertussis-specific IgG in infants in days was 29.4 (95% CI 27.3–31.7) for PT, 29.8 (95% CI 27.7–32.2) for FHA, 31.2 (95% CI 28.9–33.7) for PRN, and 35.8 (95% CI 30.1–44.3) for FIM.ConclusionThe half-life of pertussis-specific antibodies in infants induced by maternal Tdap vaccination (29–36 days) is shorter than previously reported. Understanding how the durability of passively-acquired antibodies impacts infant susceptibility to pertussis and response to primary vaccination is critical to refine prevention strategies.     

Levels of antibodies specific to diphtheria toxoid,tetanus toxoid,and Haemophilus influenzae type b in healthy children born to Tdap-vaccinated mothers

IntroductionVaccination of pregnant women protects both women and their newborns against some infectious diseases. Thailand implemented tetanus toxoid (TT) vaccination of pregnant women in 1977, which was replaced by tetanus–diphtheria toxoid (dT) vaccination in 2005. The tetanus–diphtheria–acellular pertussis (Tdap) vaccine has been recommended for pregnant women at 27–36 weeks of gestation since 2012 in several countries. Data on antibody responses to diphtheria toxoid (DT), TT, and Hemophilus influenzae type b (Hib) induced by combined vaccines in children born to TT-vaccinated and/or Tdap-vaccinated mothers are limited.Material and methodsWe investigated anti-DT, anti-TT, and anti-Hib IgG responses in a cohort of Thai children (ClinicalTrial.gov NCT02408926) born to mothers who received a TT-containing and/or the Tdap vaccine during pregnancy. Children born to Tdap-vaccinated mothers were randomized to receive either a hexavalent (Infanrix-hexa) or pentavalent (Quinvaxem) vaccine, whereas children born to TT-vaccinated mothers received only Quinvaxem vaccine at 2, 4, 6, and 18 months of age. IgG levels were evaluated at birth (cord blood), 2 (pre-primary), 7 (post-primary), 18 (pre-booster), and 19 months of age (post-booster) using a commercially available enzyme-linked immunoassay.ResultsSeroprotective concentrations of anti-DT, anti-TT, and anti-Hib IgG were achieved in >90% and >99% of children following primary and booster vaccination, respectively. Among children born to Tdap-vaccinated mothers, the pentavalent vaccine induced higher levels of anti-Hib IgG than the hexavalent vaccine after primary and booster vaccination. Significantly higher anti-Hib IgG levels were observed among children receiving the pentavalent vaccine and who were born to TT-vaccinated mothers than among children receiving the pentavalent vaccine and born to Tdap-vaccinated mothers after primary and booster vaccination.ConclusionsVaccination with a TT-containing and/or the Tdap vaccine during pregnancy did not compromise the seroprotection rate achieved following primary and booster immunization in individuals receiving either the pentavalent or hexavalent vaccine.     

Immunogenicity of a single dose of reduced-antigen acellular pertussis vaccine in a non-vaccinated adolescent population

German adolescents (n=123) without previous pertussis vaccination, no history of pertussis and low IgG-anti-pertussis-toxin (PT) levels received one dose of the Tdap vaccine Boostrix. Blood samples were taken before, and 5-12 days and 29-49 days after vaccination. IgG- and IgA-anti-PT, IgG- and IgA-anti filamentous hemagglutinin, IgG-anti-pertactin, IgG-anti-tetanus-toxin, and IgG-anti-diphtheria-toxin were measured by ELISA. 88.6% of subjects had an immune response to PT, and all vaccinees had an immune response to at least one pertussis antigen 29-49 days after vaccination. IgA-anti-PT and IgA-anti-FHA responses were found in 43 and 81% of subjects, respectively. This study shows that in unvaccinated German adolescents pertussis immunity can be achieved by a single dose of Tdap.     

Pertussis Immunisation in Pregnancy Safety (PIPS) Study: A retrospective cohort study of safety outcomes in pregnant women vaccinated with Tdap vaccine

BackgroundNew Zealand has funded the administration of tetanus, diphtheria and acellular pertussis (Tdap) vaccine during pregnancy to prevent infant pertussis since 2013. The aim of this study was to assess the safety of Tdap vaccine administered to pregnant women as part of a national maternal immunisation programme.MethodsWe conducted a national retrospective observational study using linked administrative New Zealand datasets. The study population consisted of pregnant women eligible to receive funded Tdap vaccination from 28 to 38 weeks gestation in 2013. Primary study outcomes were based on prioritised adverse events for the assessment of vaccine safety in pregnant women, as defined by WHO and Brighton Collaboration taskforces. We examined the effect of Tdap vaccination on prioritised maternal outcomes using Cox proportional hazard models. Adjusted hazard ratios controlled for key confounding variables.ResultsIn the cohort of 68,550 women eligible to receive funded antenatal Tdap vaccination during 2013, 8178 (11.9%) were vaccinated and 60,372 (88.1%) were unvaccinated. The use of Tdap in pregnancy was not associated with an increase in the rate of primary outcomes, including preterm labour; pre-eclampsia; pre-eclampsia with severe features; eclampsia; gestational hypertension; fetal growth restriction; or post-partum haemorrhage. Tdap also did not increase secondary outcomes, including gestational diabetes mellitus; antenatal bleeding; placental abruption; premature rupture of membranes; preterm delivery; fetal distress; chorioamnionitis; or, maternal fever during or after labour. Lactation disorders was the only secondary maternal outcome with a significantly increased hazard ratio. Tdap vaccine had a protective effect on pre-eclampsia with severe features, preterm labour, preterm delivery, and antenatal bleeding.ConclusionWe did not detect any biologically plausible adverse maternal outcomes following Tdap vaccination during pregnancy. This study provides further assurance that Tdap administration during pregnancy is not associated with unexpected safety risks.     

Humoral immunity 10 years after booster immunization with an adolescent and adult formulation combined tetanus,diphtheria, and 5-component acellular pertussis vaccine in the USA

BackgroundIn a prospective, randomized pivotal phase III clinical trial, the immunogenicity and reactogenicity of a tetanus-diphtheria-acellular pertussis vaccine (Tdap) and a tetanus-diphtheria vaccine (Td) vaccine were studied in participants aged 11–64 years. Here we report antibody persistence through 10 years after vaccination.MethodsParticipants who received Tdap or Td in the original phase III trial and provided pre- and post-vaccination serum samples were recruited to donate sera at 1, 3, 5 and 10 years post-vaccination. Antibody concentrations were measured using standard assay techniques.ResultsInitially, 1457 Tdap and 1152 Td recipients were included; of these, 175 persons from Tdap group were available at the final study bleed point. Nearly all adolescents in both groups had diphtheria antibody levels ≥0.1 IU/mL 1 month after vaccination, which were maintained in ≥95% of vaccinees at 5 and 10 years. Among adults, ≥94% had diphtheria antibody levels ≥0.1 IU/mL 1 month after vaccination, which were maintained in ≥80% at 5 and 10 years. Nearly all participants had tetanus antibodies ≥0.1 IU/mL throughout the study. PT antibodies declined to pre-vaccination levels approximately 5 years post-vaccination; FHA, PRN and FIM antibodies waned at 5 and 10 years but remained several-fold higher than pre-vaccination levels.ConclusionsTdap and Td provide long-lasting protective immune responses against diphtheria and tetanus. Pertussis antibodies following Tdap generally exceeded pre-vaccination levels throughout the study, but showed substantial waning. These data may inform discussion of the need for repeat Tdap booster vaccinations among adults.Trial registrationThe original phase III clinical trial, as well as the 1-, 3-, and 5-year serology follow-up studies were conducted prior to mandatory registration. The 10-year serology follow-up data collection was performed as part of a repeat Tdap administration clinical trial that was registered under clinicaltrials.gov number NCT01439165.     

Immunogenicity and safety of a tetanus toxoid,reduced diphtheria toxoid and three-component acellular pertussis vaccine in adults 19–64 years of age

Purpose

This study was conducted to assess the immunogenicity and safety of a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine containing three pertussis antigens (Boostrix^®, Tdap3v), currently licensed in the US for use in adolescents 10–18 years of age, in adults 19–64 years of age.

Methods

2284 healthy adults, aged 19–64 years, were randomized to receive a single dose of Tdap vaccine, either Tdap3v or a five-pertussis component Tdap vaccine (Adacel^®, Tdap5v) licensed for adult use in the US. Blood samples were taken before and 1 month after vaccination. Reactogenicity was assessed for 15 days after vaccination.

Results

Tdap3v was comparable to Tdap5v in eliciting seroprotective levels of antibodies to diphtheria and tetanus toxoids, with >98% of subjects having post-vaccination seroprotective antibody levels (≥0.1 IU/mL) against diphtheria or tetanus toxoids. The pertussis components of Tdap3v were shown to be immunogenic in adults, with booster responses to pertussis toxoid (PT), filamentous hemagglutinin (FHA), and pertactin (PRN) observed in 77.2%, 96.9%, and 93.2%, respectively, of Tdap3v recipients, and in 47.1%, 94.0%, and 91.7%, respectively, of Tdap5v recipients. Anti-pertussis antibody GMCs in Tdap3v recipients exceeded those observed in infants following primary DTaP vaccination, in whom efficacy against pertussis disease was subsequently demonstrated. Injection site reactions (pain, redness, and swelling) and fever ≥37.5 °C (99.5 °F) were reported significantly more often (p < 0.05) by Tdap5v recipients than by Tdap3v recipients. Fatigue preventing normal daily activities was reported by a small but significantly greater percentage of Tdap3v recipients (2.5%) than Tdap5v recipients (1.2%, p < 0.05).

Conclusion

In adult recipients, Tdap3v was comparable to an approved Tdap vaccine in providing seroprotection against diphtheria and tetanus, and produced immune responses to pertussis antigens consistent with protection against disease. The overall safety profile of Tdap3v was generally comparable to that of Tdap5v [NCT #106316].     

A phase 2 randomized controlled dose-ranging trial of recombinant pertussis booster vaccines containing genetically inactivated pertussis toxin in women of childbearing age

BackgroundA phase 2 randomized-controlled safety and immunogenicity trial evaluating different doses of recombinant acellular pertussis vaccine containing genetically-inactivated pertussis toxin (PT_gen) was conducted in women of childbearing age in Thailand to identify formulations to advance to a trial in pregnant women.MethodsA total of 250 women were randomized 1:1:1:1:1 to receive one dose of one of three investigational vaccines including low-dose recombinant pertussis-only vaccine containing 1 μg PT_gen and 1 μg FHA (ap1_gen), tetanus, reduced-dose diphtheria (Td) combined to ap1_gen (Tdap1_gen) or combined to recombinant pertussis containing 2 μg PT_gen and 5 μg FHA (Tdap2_gen), or one dose of licensed recombinant TdaP vaccine containing 5 μg PT_gen and 5 μg FHA (Boostagen®, TdaP5_gen) or licensed Tdap vaccine containing 8 μg of chemically inactivated pertussis toxoid (PT_chem), 8 μg FHA, and 2.5 μg pertactin (PRN) (Boostrix^TM, Tdap8_chem). Serum Immunoglobulin G (IgG) antibodies against vaccine antigens were measured before and 28 days after vaccination by ELISA. To advance to a trial in pregnant women, formulations had to induce a PT-IgG seroresponse rate with a 95% confidence interval (95% CI) lower limit of ≥ 50%.ResultsBetween 5 and 22 July 2018, a total of 250 women with median age of 31 years were enrolled. Post-vaccination PT-IgG seroresponse rates were 92% (95% CI 81–98) for ap1_gen, 88% (95% CI 76–95) for Tdap1_gen, 80% (95% CI 66–90) for Tdap2_gen, 94% (95% CI 83–99) for TdaP5_gen, and 78% (95% CI 64–88) for Tdap8_chem. Frequencies of injection site and systemic reactions were comparable between the groups. No serious adverse events were reported during the 28-day post-vaccination period.ConclusionsAll recombinant acellular pertussis vaccines were safe and immunogenic in women of childbearing age, and all met pre-defined immunogenicity criteria to advance to a trial in pregnant women.Clinical Trial Registration: Thai Clinical Trial Registry, TCTR20180321004.     

Increasing antepartum Tdap vaccine administration: A quality improvement initiative

The Centers for Disease Control and Prevention (CDC) recommends antepartum Tdap vaccination for women with each pregnancy to protect themselves and their vulnerable infants through transplacental transfer of maternal antibodies. Our aim was to increase the rate of antepartum Tdap vaccine administration by 20%. Obstetricians were surveyed to identify their present approaches and barriers to antepartum Tdap vaccine administration to help guide the development of our intervention. Limited staff training, lack of vaccine on site, and cost were the most commonly identified barriers. Using these survey responses, existing literature, and brainstorming conversations with colleagues, an interdisciplinary workgroup then created a fishbone analysis and developed a 5-step intervention to address these barriers: (1) educate providers and patients on Tdap and pertussis; (2) increase Tdap availability to all pregnant women; (3) remind staff of the established Tdap standing order to facilitate administration; (4) encourage obstetricians to offer Tdap; (5) transfer documentation of Tdap administration from office to hospital. To monitor changes in the process over 15 months of pre- and post-intervention, data were collected from monthly chart audits and a two-phase control chart was created. The main outcome measure was proportion of eligible women who received Tdap during current pregnancy. In the pre-intervention period, 362 of 636 eligible women (56.9%) received Tdap during their current pregnancy; in the post-intervention period, 457 of 708 eligible women (64.5%) received Tdap during their current pregnancy. This absolute difference of 7.6% (64.5% vs. 56.9%, p < 0.01) represents a 13.4% relative increase (64.5%/56.9%) in the proportion of clinically eligible pregnant women who received Tdap. This represents a clinically and statistically significant increase in the rate of antepartum Tdap immunization. More research is needed to further understand obstetric barriers and maternal refusal of antepartum Tdap administration.